Antibiotics are a series of chemicals that can inhibit and kill pathogens at a certain concentration, including metabolites produced by microorganisms, animals and plants, and chemically synthetic or semi-synthetic compounds. Antibiotics not only refer to anti-bacterial substances, but also to anti-tumor, anti-viral, anti-parasitic substances and the like. Antibiotics are an important pillar that enables us to prolong life, live healthier and benefit from modern medicine.
With the large amount of antibiotics' emergence and widespread use thereof, the problem of antibiotic resistance has become increasingly prominent, and the speed of developing drug resistance has become faster and faster. The speed is fast and the spectrum of drug resistance is wide, which is staggering.
More than 95% of Staphylococcus aureus is resistant to almost all of penicillins and 90% methicillin worldwide. More than 80% of E. coli is not sensitive to one third of third-generation cephalosporins, and is resistant to 90% of fluoroquinolone. Not only that, many bacteria becomes to develop multiple drug resistance. In the clinic, Staphylococcus aureus, which is resistant to methicillin, is also resistant to amoxicillin, levofloxacin, rifampicin, and even vancomycin. E. coli and K. pneumoniae have formed new resistance mechanism, producing New Delhi metallo-β-lactamase 1 (NDM-1) which is resistant to almost all of β-lactam drugs.
Chemotherapy is currently one of the most important means of clinical treatment for malignant tumors. However, because tumor cells often become resistant to chemotherapeutic drugs, patients are no longer sensitive to chemotherapy, which ultimately leads to failure of treatment. Although the epidermal growth factor receptor (EGFR) inhibitors such as Iressa and Tarceva and the like have achieved great success in the treatment of non-small cell lung cancer, the drug resistance problem has become increasingly prominent, and half of the drug resistance is derived from the EGFR T790M mutation. Hepatocellular carcinoma is one of the most common malignant cancers in the world and is generally highly tolerant to chemotherapeutic drugs. Nearly half of breast cancers are resistant to Herceptin from the beginning.
In view of the increasingly severe situation of antibiotic resistance, developing antibiotics with new mechanisms of action is imminent. Peptide deformylase inhibitor is one of the new targets for research in recent years. Peptide deformylase (PDF) is a metalloproteinase which is not only widely found in bacteria but also in Plasmodium falciparum and humans. In the process of proteins synthesis in bacterial, PDF can remove formyl groups from methionine, allowing functionalized proteins synthesizd in bacteria. The process of removing formyl groups is a necessary process for proteins synthesis in bacteria. However, the main protein synthesis process in human cells does not depend on the process of formyl removal. This difference on protein synthesis between bacteria and human makes bacterial PDF a potential target for anti-bacterial drugs. By chelation with the PDF enzyme, PDF inhibitor could prevent bacteria from undergoing the deformylation step in the process of protein synthesis, thereby selectively inhibiting the growth of bacteria. Compared with normal human cells, human PDF gene in various of cancer cells such as colorectal cancer, lung cancer, prostate cancer and the like are over-expressed, which can affect the energy balance of the cancer cells by inhibiting the peptide deformylase in mitochondria in the cells, so that mitochondrial membrane can be depolarized, ATP can be exhausted and cell apoptosis can be promoted. PDF inhibitors can be developed into broad-spectrum anti-bacterial agents with good anti-bacterial activity and anti-cancer drugs with anti-cancer activity.
PDF inhibitors encompassed structures: Metal Binding Group (MBG) and peptidomimetic or non-peptide backbones containing P1, P2 and P3 moieties (formula (a): general structure for PDF inhibitor).

Although many PDF inhibitors have been developed for preclinical studies, and even some compounds have entered into the clinic (e.g. formulas (b)˜(d)), due to the nature of the compounds themselves, they showed poor activity, or clinical toxicity, and ultimately could not successfully appear on the market. For example, actinomycin Actinonin is the first PDF inhibitor to be discovered that exhibits good activity against Gram-positive and Gram-negative bacteria; but due to instability in metabolism in the body, it ultimately exhibits no activity in vivo. For LBM415, entered into Phase I clinical trial of anti-bacterial activity, which has broad-spectrum activity, and could cause methemoglobinemia at a high dose (Clin. Pharmacol. Ther. 2011, 90, 256). For GSK1322322, due to the presence of metabolically active compounds which could cause toxicity to the body, the Phase I clinical study of anti-bacterial activity also had been terminated by FDA for similar reasons (see project No. NCT01818011 in ClinicalTrials.gov for reasons of clinical study termination).
